Non-narcotic analgesics, most of which are also known as non-steroidal anti-inflammatory drugs (NSAID), are widely administered orally in the treatment of mild to severe pain. Within this class, the compounds vary widely in their chemical structure and in their biological profiles as analgesics, anti-inflammatory agents and antipyretic agents. Aspirin, acetaminophen and phenacetin have long been among the most commonly used members of this group; more recently, however, a large number of alternative non-narcotic agents offering a variety of advantages over the earlier drugs have been developed. Tolerance or addiction to these drugs is not generally a problem with their continuous use in the treatment of pain or in the treatment of acute or chronic inflammatory states (notably, rheumatoid arthritis and osteoarthritis); nevertheless, these drugs generally have a higher potential for adverse side-effects at the upper limits of their effective dose ranges. Moreover, above each drug's upper limit or ceiling, administration of additional drug does not usually increase the analgesic or anti-inflammatory effect. Among the newer compounds in the non-narcotic analgesic/nonsteroidal anti-inflammatory group are compounds such as diflunisal (Dolobid.RTM.), zomepirac sodium (Zomax.RTM.), ibuprofen (Motrin.RTM.), naproxen (Naprosyn.RTM.), fenoprofen (Nalfon.RTM.), piroxicam (Felden.RTM.), flurbiprofen, mefenamic acid (Ponstel.RTM.) and sulindac. See also Physicians' Desk Reference, 35th edition, 1981, and The Merck Index, ninth edition, Merck & Co., Rahway, New Jersey (1976), for information on specific nonsteroidal anti-inflammatory agents. Also see, generally, Wiseman, "Pharmacological Studies with a New Class of Nonsteroidal Anti-Inflammatory Agents--The Oxicams--With Special Reference to Piroxicam (Feldene.RTM.)", The American Journal of Medicine, Feb. 16, 1982: 2-8; Foley et al, The Management of Cancer Pain, Volume II--The Rational Use of Analgesics in the Management of Cancer Pain, Hoffman-LaRoche Inc., 1981; and Cutting's Handbook of Pharmacology, sixth edition, ed. T. Z. Czaky, M.D., Appleton-Century-Crofts, New York, 1979, Chapter 49: 538-550.
Narcotic analgesics are often used when pain control with non-narcotic analgesics is ineffective. While the drugs in this group vary considerably in their chemical structures and pharmacological properties, almost all suffer the disadvantages of tolerance and possible addiction with continued usage. Within the narcotic analgesic group, the drugs can be classified as narcotic agonists or narcotic antagonists. Narcotic agonists include the morphine group, the meperidine group and the methadone group. While some narcotic antagonists are pure antagonists (which are not analgesics), other narcotic antagonists are agonist-antagonists (i.e. antagonists with analgesic properties); (The agonist-antagonists are generally categorized as morphine-like or nalorphine-like). Many of the narcotic analgesics are not effective orally, but are rather used parenterally. The orally active narcotic analgesics include such compounds as codeine, oxycodone, levorphanol (Levo-Dromoran.RTM.), meperidine (Demerol.RTM.), propoxyphene hydrochloride (Darvon.RTM.), propoxyphene napsylate (Darvon-N.RTM.), methadone, propiram, buprenorphine, pentazocine (Talwin.RTM.), nalbuphine (Nubain.RTM.) and butorphanol (Stadol.RTM.). For more specific information on these compounds, see Physicians' Desk Reference, 35th edition, 1981, and The Merck Index, ninth edition, Merck & Co., Inc., Rahway, New Jersey (1976). Also see, generally, the Foley et al reference cited hereinabove and Cutting's Handbook of Pharmacology, sixth edition, ed. T. Z. Czaky, M.D., Appleton-Century-Crofts, New York, 1979, Chapter 50: 551-566.
Xanthine alkaloids, including caffeine, theophylline and theobromine are ubiquitously distributed in plants such as the seeds of Coffea arabica and related species, the leaves of Thea sinensis, the seeds of Theobroma cacao, the nuts of the tree Cola acuminata and the like. Extracts of these naturally occurring substances have been used throughout history as beverages and the pharmacologically significant nervous system stimulant properties of such concoctions have long been recognized.
Xanthine itself is 3,7-dihydro-1H-purine-2,6-dione. Thus, chemically, the xanthine and xanthine derivatives are structurally related to uric acid and purine. Caffeine (1,3,7-trimethylxanthine), theophylline (1,3-dimethylxanthine) and theobromine (3,7-dimethylxanthine) represent the alkaloids most frequently associated with the expression xanthine. However, numerous other xanthine derivatives have been isolated or synthesized. See, for example, Bruns, Biochem. Pharmacol., 30, 325-333, 1981 describing more than one hundred purine bases and structurally related heterocycles relative to adenosine antagonism; Daly, J. W., "Adenosine Receptors: Targets for Future Drugs", J. Med. Chem., 25 (3), 1982.
Pharmacologically, the xanthines represent an important class of therapeutic agents. Observed pharmacological actions include stimulation of the central nervous system, relaxation of smooth muscle constrictions of the smaller bronchi and other smooth muscles, dilation of the small pulmonary arteries, stimulation of cardiac muscle with increased cardiac output and the promotion of mild diuresis. It has been postulated that these actions may be related to the antagonism of adenosine or blockade of adenosine receptors, although xanthine-like pharmacological effects have been observed with compounds which have not demonstrated adenosine antagonism (see Persson et al, "Differentiation Between Bronco Dilation and Universal Adenosine Antagonism Among Xanthine Derivatives", Life Sciences, Vol. 30, pp. 2181-2189, 1982). Accordingly, other mechanisms of action may be involved relative to the pharmacological properties of the xanthine derivatives, such as, for example, the inhibition of phosphodiesterase enzymes or mobilization of intracellular calcium together with or independent of adenosine receptor antagonism. The bronchodilator effects of the xanthines, particularly, theophylline, have received considerable commercial attention and various preparations of theophylline as the anhydrous base or salts thereof including sodium acetate, sodium benzoate, sodium salicylate, calcium salicylate, etc., are available as tablets, capsules, and elixirs including sustained released forms such as Theodur.RTM., Theoclear LA.RTM., and Elixophyllin.RTM.. Other related xanthines have received widespread usage such as dyphyllin (Dilor.RTM., Lufyllin.RTM.), and oxytriphylline (Choledyl.RTM.).
Various xanthine derivatives have been heretofore used in combination with other therapeutically active compounds including, ephedrine, amobarbital, phenobarbital, potassium iodide, guaifenesin, and the like available as Quibron Plus.RTM., Synophylate-GG.RTM., Tedra.RTM., Amesec.RTM., etc. However, the xanthine derivatives to which the present invention relates have not, heretofore, been suggested for formulation in pharmaceutical compositions in combination with non-narcotic analgesics, non-steroidal anti-inflammatory drugs and/or narcotic analgesics.
Caffeine, or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione, has the structural formula ##STR1## This substance has been used alone, intravenously, in the treatment of headaches and has also been used in combination with selected drugs. Compositions containing one or more of the analgesics aspirin, acetaminophen and phenacetin in combination with varying amounts of caffeine have been marketed in the past; in several cases, such non-narcotic analgesic/caffeine combination products have further included one of the narcotic analgesics codeine, propoxyphene or oxycodone. Examples of these combinations include the products known commercially as Excedrin.RTM., SK-65.RTM. Compound, Darvon.RTM. Compound, Anacin.RTM., A.P.C., and A.P.C. with Codeine, Tabloid.RTM. Brand. The nonsteroidal analgesic components of these mixtures have the following structural formulas: ##STR2##
The three narcotic analgesics which have occasionally been added to the aspirin/phenacetin/acetaminophen/caffeine combinations have the following structural formulas: ##STR3## As far as the present inventors know, however, the art has never suggested that caffeine be added to a narcotic analgesic to contribute to its analgesic effect.
Many workers have sought to demonstrate the efficacy of the aspirin/phenacetin/acetaminophen/caffeine combination products. An extensive review of the literature on caffeine and analgesics has been published ["Over-The-Counter Drugs: Establishment of a Monograph for OTC Internal Analgesic, Antipyretic and Antirheumatic Products," Federal Register, 1977, 42 (131): 35482-35485] and several relevant additional articles have appeared. Most animal studies on caffeine analgesia have been performed on the rat. Williams (Toxicology and Applied Pharmacology, 1959, 1: 447-453) utilized experimental pain and found that caffeine alone exerted analgesic effects on rats and when combined with aspirin; the effect appeared additive but not potentiating. Vinegar et al (Proceedings of the Society for Experimental Biology and Medicine, 1976, 151: 556-560), ten years later, found that in the rat caffeine potentiates the acute anti-inflammatory and analgesic activity of aspirin. Siegers (Pharmacology, 1973, 10: 19-27) studied the effect of oral doses of caffeine (10, 50 and 100 mg/kg) given to rats together with acetaminophen and found that caffeine inhibited its absorption and lowered its serum concentration. He suggested that delayed stomach emptying as a result of the relaxing effect of caffeine on gastric smooth muscle was probably the cause of the diminished absorption of orally administered drugs in the presence of caffeine. Despite this finding, acetaminophen analgesia was not decreased by caffeine. In agreement with Williams and Vinegar and his associates, Siegers found that caffeine itself had analgesic activity. Only in the lowest dose of caffeine studied, a dose at which analgesia was not exhibited, was there a reduction in the acetaminophen induced analgesia. In a more recent paper, Seegers et al (Arch. Int. Pharmacodyn., 1981, 251: 237-254) demonstrated an anti-inflammatory, analgesic effect of caffeine in rats. He also found that the combination of caffeine, aspirin and acetaminophen as well as the combination of caffeine, aspirin and phenacetin at low doses produced anti-inflammatory, analgesic effects which are at least as great as would be expected on the basis of addition, while at high doses, the results suggested potentiation. Citing the work of Giertz and Jurna (Naturwissenschaften, 1957, 44: 445), and Fuchs and Giertz (Arzneimittelforsch, 1960, 10: 526-530), who observed that caffeine induced analgesia in assays in mice in which inflammation was not involved, Seegers asserted that, "it seems safe to assume that the analgesic activity of caffeine consists of at least two components, one independent of and another one dependent on its anti-inflammatory activity."
The earliest relevant study in humans was reported by Wallenstein (Proceedings of the aspirin symposium, held at the Royal College of Surgeons, London, 1975). Two tablets of a combination in which each tablet contained aspirin 210 mg, acetaminophen 150 mg and caffeine 30 mg, clearly and significantly produced more analgesia than the combination without caffeine. The one tablet dose of the combination had higher mean scores than either component alone, but was not superior to the combination without caffeine. Wallenstein speculated that, "dosage may be an important factor, and caffeine may simply be ineffective much below the 60 mg dose". Booy (Nederlands Tijdschrift Voor Tandheelkinde, 1972, 79: 69-75) studied pain relief on each of two days after tooth extraction. Patients who reported "great pain" on the first day obtained more pain relief from 1000 mg of acetaminophen plus 100 mg of caffeine than from 1000 mg of acetaminophen alone. On the second day this difference was not found, although on both days all treatments were superior to placebo. Lim et al (Clin. Pharmacol. Ther., 1967, 8: 521-542), reporting a study in which experimental pain was induced in the subjects by bradykinin, observed that the combination of aspirin 520 mg and acetaminophen 260 mg given orally could not be distinguished from placebo, whereas the same combination in lesser quantities, aspirin 325 mg and acetaminophen 162.5 mg plus caffeine 32.5 mg was significantly different from placebo at 15, 60, 75, 105, and 120 minutes after taking the drug. A double-blind, crossover study of 216 patients by Wojcicki et al [Archivum Immunologiae et Therapeae Experimentalis, 1977, 25(2): 175-179] compared the activity of 1000 mg of acetaminophen plus 100 mg of caffeine against the same quantity of acetaminophen alone. One group of patients in the trial were suffering severe and frequently occurring idiopathic headache and a second group had moderate post-operative orthopedic pain. The authors concluded that the relief of pain was far greater with the caffeine combination than with acetaminophen alone or with aspirin alone. Jain et al (Clin. Pharmacol. Ther., 1978, 24: 69-75) first studied 70 postpartum patients with moderate to severe uterine cramp and/or episiotomy pain and then a second group of 70 patients limited to severe pain only. Comparing 800 mg aspirin plus 64 mg of caffeine to 650 mg aspirin alone, these authors concluded that in patients with severe episiotomy pain the combination is the more effective analgesic.
Caffeine use in the treatment of headache has a long history. The FDA Advisory Panel, in its review of caffeine [Federal Register, 1977, 42 (131): 35482-35485] argued that the known biochemical effect of caffeine on small blood vessels provides a plausible explanation for its effectiveness in treating headache associated with cerebral blood vessels. Recently Sechzer [Curr. Therapy Research, 1979, 26(4)] found that the intravenous administration of caffeine sodium benzoate rapidly provided relief in the majority of patients experiencing headache resulting from dural puncture or spinal anesthesia. The author, referring to the literature on the mechanism of action of caffeine on cerebral blood flow and on cerebral vascular tone, argues from the opposite perspective of the Panel that the analgesic relief obtained implies that an intracranial vascular component is the primary factor in such headaches.
Changes in mood and over-all sense of "well-being" after administration of caffeine have been widely reported in the literature. Beginning in the early part of this century, Hollingsworth (Arch. Psychol., 1912, 22: 1) reported beneficial motor and mental effects from 65 to 130 mg of caffeine, and tremor, poor motor performance, and insomnia caused by 390 mg of caffeine. Many studies over the past 70 years have confirmed those findings. Review articles on the xanthines [Ritchie, J. M., "Central nervous system stimulants. 2. The xanthines," Goodman, L. S. & Gilman, A. (Eds.), The pharmacological basis of therapeutics, 4th Ed., New York: Macmillan Co., 1970; Stephenson, P. E., "Physiologic and psychotropic effects of caffeine on man," J. Amer. Diet. Assoc., 1977, 71(3): 240-247] report that doses of 50 to 200 mg of caffeine result in increased alertness, decreased drowsiness, and lessened fatigue. Doses in the range of 200 to 500 mg may produce headaches, tremor, nervousness and irritability.
After extensively reviewing the relevant literature, the most significant contributions of which are summarized above, the FDA Advisory Panel in 1977 concluded that caffeine when used as an analgesic adjuvant was safe, but that there was insufficient data to demonstrate that caffeine contributes anything to the action of the analgesic [Federal Register, 1977, 42 (131): 35482-35485]. The Panel stated:
Unfortunately, the information and data submitted, fail to demonstrate conclusively that caffeine in combination is effective as an analgesic, antipyretic and/or antirheumatic ingredient. The Panel finds there is little evidence to show that this ingredient even contributes to these pharmacological effects in the clinical situation.
This remains the official position on the question up to the present time. Consequently, many of the analgesic/caffeine combination products previously available are no longer on the market.
In addition to the few prior art instances of selected non-narcotic analgesic/caffeine combinations further containing a selected narcotic analgesic (which three-component combinations have already been discussed hereinabove), there also are examples in the art of two-component combinations of selected non-narcotic analgesics with selected narcotic analgesics. Known combinations of this type include Darvon.RTM. with A.S.A..RTM. (propoxyphene hydrochloride and aspirin), Darvon-N.RTM. with A.S.A..RTM. (propoxyphene napsylate and aspirin), aspirin with codeine, Talwin.RTM. Compound (pentazocine hydrochloride, oxycodone and aspirin), Percodan.RTM. (oxycodone hydrochloride, terephthalate and aspirin) and nalbuphine with acetaminophen, the last-mentioned combination being disclosed in U.S. Pat. No. 4,237,140. The general principle of use of a combination of drugs to produce additive analgesic effects is known to those skilled in the art; for example, Foley et al, The Management of Cancer Pain, Volume II--The Rational Use of Analgesics in the Management of Cancer Pain, Hoffman-LaRoche Inc., 1981, suggest such combination and specifically point out that 650 mg aspirin or acetaminophen regularly added to the standard narcotic dose will often enhance the analgesic effect without requiring higher doses of the narcotic. Such additive effects have been reported earlier by Houde et al, Clin. Pharm. Ther. 1(2): 163-174(1960) for intramuscularly administered morphine sulfate given with orally administered aspirin. As far as the present inventors know, however, the art does not suggest any two-component compositions of a narcotic analgesic and caffeine; it also does not suggest any improvements in the analgesic response to be derived from co-administering caffeine with any narcotic analgesic. Likewise, the inventors are not aware of any two-component compositions of a narcotic analgesic and a xanthine derivative (other than caffeine) to which the present invention further pertains or any prior art recognized improvements in analgesic response to be derived from the concommitant administration of a xanthine type agent with any narcotic analgesic.